Small molecules facilitate the reprogramming of mouse fibroblasts into pancreatic lineages.
Small molecules facilitate the reprogramming of mouse fibroblasts into pancreatic lineages.
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DOI：
10.1016/j.stem.2014.01.006
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发表时间：
2014-02-06
期刊：
影响因子：
23.9
通讯作者：
Ding S
中科院分区：
文献类型：
--
作者：
Li K;Zhu S;Russ HA;Xu S;Xu T;Zhang Y;Ma T;Hebrok M;Ding S
胰岛β细胞对1型糖尿病的治疗有很大的兴趣。β细胞的生成已经存在许多策略，但将非内胚层细胞重编程为β细胞的一般方法可能在各种情况下提供有吸引力的替代方案。在这里，我们描述了一种循序渐进的方法，其中多能重编程因子与可溶性分子的独特组合一起在成纤维细胞中短暂表达，以产生不经过多能状态的最终内胚层样细胞。这些内胚层样细胞随后在体外通过进一步的小分子组合被引导到胰腺谱系。由此产生的胰腺祖细胞样细胞可以在体内成熟为所有三种胰腺谱系的细胞，包括有助于改善高血糖的功能分泌胰岛素的β样细胞。因此，我们的发现可能为生成大量用于疾病建模的功能性β细胞以及最终的基于细胞的治疗提供一种有用的方法。
Pancreatic β cells are of great interest for the treatment of type 1 diabetes. A number of strategies already exist for the generation of β cells, but a general approach for reprogramming nonendodermal cells into β cells could provide an attractive alternative in a variety of contexts. Here, we describe a stepwise method in which pluripotency reprogramming factors were transiently expressed in fibroblasts in conjunction with a unique combination of soluble molecules to generate definitive endoderm-like cells that did not pass through a pluripotent state. These endoderm-like cells were then directed toward pancreatic lineages using further combinations of small molecules in vitro. The resulting pancreatic progenitor-like cells could mature into cells of all three pancreatic lineages in vivo, including functional, insulin-secreting β-like cells that help to ameliorate hyperglycemia. Our findings may therefore provide a useful approach for generating large numbers of functional β cells for disease modeling and, ultimately, cell-based therapy.